Skip to main content
PMC home page
Brain Pathology logoLink to Brain Pathology
. 2006 Apr 5;14(1):51–58. doi: 10.1111/j.1750-3639.2004.tb00497.x

Lesion‐associated Expression of Transforming Growth Factor‐Beta‐2 in the Rat Nervous System: Evidence for Down‐regulating the phagocytic Activity of Microglia and Macrophages

Guido Stoll 1,✉, Michael Schroeter 2, Sebastian Jander 2, Heike Siebert 3, Anja Wollrath 3, Christoph Kleinschnitz 1, Wolfgang Brück 3
PMCID: PMC8095793  PMID: 14997937

Abstract

The mechanisms that control the phagocytic activities of microglia and macrophages during disorders of the nervous system are largely unknown. In the present investigation, we assessed the functional role of transforming growth factor (TGF)β2 in vitro and studied TGFβ‐2mRNA and protein expression two CNS lesion paradigms in vivo characterized by fundamental differences in microglia/macrophage behaviour: optic nerve crush exhibiting slow, and focal cerebral ischemia exhibiting rapid phagocytic transformation. Furthermore, we used sciatic nerve crush injury as a PNS lesion paradigm comparable to brain ischemia in its rapid phagocyte response. In normal and degenerating optic nerves, astrocytes strongly and continuously expressed TGF‐β2 immunoreactivity. In contrast, TGF‐β2 was downregulated in Schwann cells of degenerating sciatic nerves, and was not expressed by reactive astrocytes in the vicinity of focal ischemic brain lesions during the acute phagocytic phase In line with its differential lesion‐associated expression pattern, exogenous TGF‐β2 suppressed spontaneous myelin phagocytosis by microglia/macrophages in a mouse ex vivo assay of CNS and PNS Wallerian degeneration. In conclusion, we have identified TGF‐β2 as a nervous system intrinsic cytokine that could account for the differential regulation of phagocytic activities of microglia and macrophages during injury.

Full Text

The Full Text of this article is available as a PDF (914.0 KB).

References

  • 1. Benveniste EN ( 1997. ) Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis . J Mol Med 75 : 165 – 173 . [DOI] [PubMed] [Google Scholar]
  • 2. Blobe GC , Schiemann WP , Lodish HF ( 2000. ) Role of transforming growth beta in human disease . N Engl J Med 342 : 1350 – 1358 . [DOI] [PubMed] [Google Scholar]
  • 3. Böttner M , Krieglstein K , Unsicker K ( 2000. ) The transforming growth factor‐betas: structure signaling, and roles system development and functions . J Neurochem 75 : 2227 – 2240 . [DOI] [PubMed] [Google Scholar]
  • 4. Brück W ( 1997. ) The role of macrophages in Wallerian degeneration Brain Pathol 7 : 741 – 752 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. Bush TG , Puvanachandra N , Hornern CH , Polito A , Ostenfeld T , Svendesen CN , Mucke L , Johnson MH , Sofroniew MV ( 1999. ) Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar‐forming, reactive astrocytes in adult transgenic mice Neuron 23 : 297 – 308 . [DOI] [PubMed] [Google Scholar]
  • 6. Buss A , Schwab ME ( 2003. ) Sequential loss of myelin proteins during Wallerian degeneration in the rat spinal cord . Glia 42 : 424 – 432 . [DOI] [PubMed] [Google Scholar]
  • 7. Chan A , Magnus T , Gold R ( 2001. ) Phagocytosis of apoptotic inflammatory cells by microglia and modulation by different cytokines: mechanism for removal of apoptotic cells in the inflamed nervous system . Glia 33 : 87 – 95 . [DOI] [PubMed] [Google Scholar]
  • 8. Da Cunha A , Vitkovic L ( 1992. ) Growth factor‐beta 1 (TGF‐beta 1) expression and regulation in rat cortical astrocytes . J Neuroimmunol 36 : 157 – 169 . [DOI] [PubMed] [Google Scholar]
  • 9. Dietrich D , Busto R , Watson BD , Scheinberg P , Ginsberg MD ( 1987. ) Photochemically induced cerebral infarction: II edema and blood‐brain‐barrier disruption . Acta Neuropath 72 : 326 – 334 . [DOI] [PubMed] [Google Scholar]
  • 10. Flanders KC , Ren RF , Lippa CF ( 1998. ) Transforming growth factor‐betas in neurodegenerative disease . Prog Neurobiol 54 : 71 – 85 . [DOI] [PubMed] [Google Scholar]
  • 11. Flaris NA , Densmore TL , Molleston MC , Hickey WF ( 1993. ) Characterization of microglia and macrophages in the central system of rats: definition of the differential expression of molecules using standard and novel monoclonal antibodies in normal CNS and in four models of parenchymal reaction . Glia 7 : 34 – 40 . [DOI] [PubMed] [Google Scholar]
  • 12. George R , Griffin JW ( 1994. ) Delayed macrophage responses and myelin clearance during wallerian degeneraton in the central nervous system: the dorsal radiculotomy model Exp Neurol 129 : 225 – 236 . [DOI] [PubMed] [Google Scholar]
  • 13. Gillen C , Jander S , Stoll G ( 1998. ) The sequential expression of mRNA for proinflammatory cytokines and interlekin‐10 in the rat peripheral nervous system: comparison between in immune‐mediated demyelination and Wallerian degeneration . J Neurosci Res 51 : 489 – 496 . [DOI] [PubMed] [Google Scholar]
  • 14. Graeber MB , Banati RB , Streit WJ , Kreutzberg GW ( 1989. ) Immunophenotypic characterization of rat brain macrophages in culture . Neurosci Lett 103 : 241 – 246 . [DOI] [PubMed] [Google Scholar]
  • 15. Jander S , Kraemer M , Schroeter M , Witte OW , Stoll G ( 1995. ) Lymphocytic infiltration and expression of intercellular adhesion molecule‐1 in photochemically induced ischemia of the rat cortex . J Cereb Blood Flow Metabol 15 : 42 – 51 . [DOI] [PubMed] [Google Scholar]
  • 16. Jander S , Schroeter M , Fischer J , Stoll G ( 2000. ) Differential regulation of microglial keratan sulfate immunoreactivity by proinflammatory cytokines and colony‐stimulating factors . Glia 30 : 401 – 410 . [DOI] [PubMed] [Google Scholar]
  • 17. Jander S , Stoll G ( 1998. ) Differential induction of interleukin‐12, interleukin‐18, and interleukin‐1beta converting enzyme mRNA in experimental autoimmune encephalomyelitis of the Lewis rat . J Neuroimmunol 91 : 93 – 99 . [DOI] [PubMed] [Google Scholar]
  • 18. Kiefer R , Streit WJ , Toyka KV , Kreutzberg GW , Hartung HP ( 1995. ) Transforming growth factor‐beta 1: a lesion‐associated cytokine of the nervous system . Int J Dev Neurosci 13 : 331 – 339 . [DOI] [PubMed] [Google Scholar]
  • 19. Kleinschnitz C , Bendszus M , Solymosi L , Toyka KV , Stoll G ( 2003. ) In vivo monitoring of macrophage infiltration in experimental ischemic brain lesions by magnetic resonance imaging . J Cereb Blood Flow Metabol 23 : 1356 – 1361 . [DOI] [PubMed] [Google Scholar]
  • 20. Koishi K , Dalzell KG McLennan Is ( 2000. ) The expression and structure TGF‐beta2 transcripts in rat muscles . Biochim Biophys Acta 311 – 319 . [DOI] [PubMed]
  • 21. Kreutzberg GW ( 1996. ) Microglia: a sensor for pathological events in the CNS . Trends Neurosci 19 : 312 – 318 . [DOI] [PubMed] [Google Scholar]
  • 22. Kuhlmann T , Wendling U , Nolte C , Zipp F , Maruschak B , Stadelmann C , Siebert H , Brück W ( 2002. ) Differential regulation of myelin phagocytosis by macrophages/microglia, involvement of target myelin, FC receptors and activation by intravenous immunoglobulins . J Neurosci Res 67 : 185 – 190 . [DOI] [PubMed] [Google Scholar]
  • 23. Lazarov‐Spiegeler O , Solomon AS , Schwartz M ( 1998. ) Peripheral nerve stimulated macrophages simulate a peripheral nerve‐like regenerative response in rat transected optic nerve . Glia 24 : 329 – 337 . [PubMed] [Google Scholar]
  • 24. Lehrmann E , Kiefer R , Christensen T , Toyka KV , Zimmer J , Hartung HP , Finsen B ( 1998. ) And macrophages are a major source of locally produced transforming growth factor beta 1 after transient middle cerebral artery occlusion in rats . Glia 24 : 437 – 448 . [DOI] [PubMed] [Google Scholar]
  • 25. Letterio JJ , Roberts AB ( 1998. ) Immune responses by TGF‐α . Annu Rev Immunol 16 : 137 – 161 . [DOI] [PubMed] [Google Scholar]
  • 26. Liedtke W , Edelmann W , Chin FC Kucherlapati R , Raine CS ( 1998. ) Experimental autoimmune encephalomyelitis in mice protein is characterized by a more severe clinical course and an infiltrative central nervous system lesion . Am J Pathol 152 : 251 – 259 . [PMC free article] [PubMed] [Google Scholar]
  • 27. Logan A , Green J , Hunter A , Jackson R , Berry M ( 1999. ) Inhibition of glial scarring in the injured rat brain by a recombinant human monoclonal antibody to growth factor‐beta2 . Eur J Neurosci 11 : 2367 – 2374 . [DOI] [PubMed] [Google Scholar]
  • 28. Menge T , Jander S , Stoll G ( 2001. ) Induction of the proinflammatory cytokine interleukin‐18 by axonal injury . J Neurosci Res 65 : 332 – 339 . [DOI] [PubMed] [Google Scholar]
  • 29. Perry VH , Brown MC , Gordon S ( 1987. ) Macrophage response to central and peripheral nerve injury. A possible role for macrophages in regeneration . J Exp Med 165 : 1218 – 1223 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. Qiu J , Cai D , Filbin MT ( 2000. ) Glial inhibition of nerve regeneration in the mature mammalian CNS . Glia 29 : 166 – 174 . [PubMed] [Google Scholar]
  • 31. Racke MK , Sriram S , Carlino J , Cannella B , Raine CS , McFarlin DE ( 1993. ) Long‐term treatment of chronic relapsing experimental allergic encephalomyelitis by transforming growth factor‐beta2 . J Neuroimmunol 46 : 175 – 184 . [DOI] [PubMed] [Google Scholar]
  • 32. Raj GV , Cupp C , Khalili K , Kim SJ , Amini S ( 1996. ) Soluble factors secreted by activated T‐lymphocytes modulate the transcription of the immunosuppressive cytokine TGF‐beta 2 in glial Cells . J cell Biochem 62 : 342 – 355 . [DOI] [PubMed] [Google Scholar]
  • 33. Reichert F , Rotshenker S ( 1996. ) Deficient activation of microglia during optic nerve degeneration . J Neuroimmunol 70 : 153 – 161 . [DOI] [PubMed] [Google Scholar]
  • 34. Sanford LP , Ormsby I , Gittenberger‐de Groot , Sariola H , Friedman R , Boivin GP , Doetschman T ( 1997. ) TGFbeta2 knockout mice have multiple developmental defects that are nonoverlapping with other TGFbeta knockout phenotypes . Development 124 : 2659 – 2670 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35. Scherer SS , Kamholz J , Jakowlew SB ( 1993. ) Axons modulate the expression of transforming growth factor‐betas in Schwann cells . Glia 8 : 265 – 276 . [DOI] [PubMed] [Google Scholar]
  • 36. Schroeter M , Jander S , Huitinga I , Witte OW , Stoll G ( 1997. ) Phagocytic response in photochemically induced infarction of the rat cerebral cortex . Stroke 28 : 382 – 386 . [DOI] [PubMed] [Google Scholar]
  • 37. Schroeter M , Jander S , Witte OW , Stoll G ( 1999. ) Heterogeneity of the microglial response in photochemically induced focal ischemia of the rat cerebral cortex . Neuroscience 89 : 1367 – 1377 . [DOI] [PubMed] [Google Scholar]
  • 38. Shull MM , Ormsby I , Kier AB , Pawlowski S , Diebold RJ , Yin M , Allen R , Sidman C , Proetzel G , Calvin D , et al. ( 1992. ) Targeted disruption of the mouse transforming growth factor‐beta 1 gene results in multifocal inflammatory disease . Nature 359 : 693 – 699 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39. Sievers J , Parwaresch R , Wottge HU ( 1994. ) Blood monocytes and spleen macropages differentiate into microglia‐like cells on monolayers of astrocytes: morphology . Glia 12 : 245 – 258 . [DOI] [PubMed] [Google Scholar]
  • 40. Smith ME , van der Maesen K , Somera FP ( 1998. ) Macrophage and microglial responses to cytokines in vitro: phagocytic activity, proteolytic enzyme release, and free radical production . J Neurosci Res 54 : 68 – 78 . [DOI] [PubMed] [Google Scholar]
  • 41. Stoll G , Griffin JW , Li CY , Trapp BD ( 1989a. ) Wallerian degeneration in the peripheral nervous system: participation of both Schwann cells and macrophages in myelin degradation . J Neurocytol 18 : 671 – 683 . [DOI] [PubMed] [Google Scholar]
  • 42. Stoll G , Jander S ( 1999. ) The role of microglia and macrophages in the pathophysiology of the CNS . Prog Neurobiol 58 : 233 – 247 . [DOI] [PubMed] [Google Scholar]
  • 43. Stoll G , Trapp BD , Griffin JW ( 1989b. ) Macrophage function during Wallerian degeneration of rat optic nerve: clearance of degenerating myelin and Ia expression . J Neurosci 9 : 2327 – 2335 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44. Streit WJ , Walter SA , Pennel NA ( 2000. ) Reactive microgliosis . Prog Neurobiol 57 : 563 – 581 . [DOI] [PubMed] [Google Scholar]
  • 45. Tanaka J , Maeda N ( 1996. ) Microglial ramification requires nondiffusible factors derived from astrocytes . Exp Neurol 137 : 367 – 375 . [DOI] [PubMed] [Google Scholar]
  • 46. Unsicker K , Flanders KC , Cissel DS , Lafyatis R , Sporn MB ( 1991. ) Transforming growth factor beta isoforms in the adult rat central and peripheral nervous system . Neuroscience 44 : 613 – 625 . [DOI] [PubMed] [Google Scholar]
  • 47. Watson BD , Dietrich WD , Busto R , Wachtel MS , Ginsberg MD ( 1995. ) Induction of reproducible brain infarction by photochemical initiated thrombosis . Ann Neurol 17 : 497 – 504 . [DOI] [PubMed] [Google Scholar]
  • 48. Yamashita K , Gerken U , Vogel P , Hossmann K , Wiessner C ( 1999. ) Biphasic expression of TGF‐beta 1 mRNA in the rat brain following permanent occlusion of the middle cerebral artery . Brain Res 836 : 139 – 145 . [DOI] [PubMed] [Google Scholar]

Articles from Brain Pathology are provided here courtesy of Wiley

RESOURCES